The biguanide antihyperglycemic agent metformin is concurrently marketed in the U.S. in the form of its hydrochloride salt (Glucophage.TM., Bristol-Myers Squibb Company).
The prior art is replete with references disclosing metformin salts of various organic or inorganic acids, for example, U.S. Pat. No. 3,174,901 discloses phosphate, sulfate, hydrobromide, salicylate, maleate, benzoate, succinate, ethanesulfonate, fumarate and glycolate salts of metformin;
U.S. Pat. No. 4,835,184 discloses the p-chloro-phenoxyacetic acid salt of metformin; PA1 French Patent Nos. 2320735 and 2037002 disclose the pamoate salt of metformin; PA1 French Patent No. 2264539 and Japanese Patent No. 66008075 disclose the orotate salt of metformin; PA1 French Patent No. 2275199 discloses the (4-chloro-phenoxy)isobutyrate salt of metformin; PA1 U.S. Pat. No. 4,080,472 discloses the clofibrate salt of metformin; PA1 U.S. Pat. No. 3,957,853 discloses the acetylsalicylate salt of metformin; PA1 French Patent No. 2220256 discloses the theophyllin-7-acetate salt of metformin; PA1 German Patent Nos. 2357864 and 1967138 disclose the nicotinic acid salt of metformin; PA1 U.S. Pat. No. 3,903,141 discloses the adamantoate salt of metformin; PA1 Japanese Patent No. 69008566 discloses the zinc-chlorophyllin salt of metformin; PA1 Japanese Patent No. 64008237 discloses hydroxy acid salts of metformin, including salts of hydroxy aliphatic dicarboxylic acids such as mesotartaric acid, tartaric acid, mesoxalic acids, and oxidized maleates; PA1 Japanese Patent No. 63014942 discloses the tannic acid salt of metformin; PA1 Japanese Patent Nos. 87005905 and 61022071 disclose the 3-methyl-pyrazole-5-carboxylic acid (or other 5-members hetercycle carboxylic acid) salt of metformin; PA1 Romanian Patent No. 82052 discloses sulfamido aryloxyalkyl carboxylic acid salts of metformin; PA1 Soviet Union Patent No. 992512 discloses the trimethoxy benzoic acid salt of metformin; PA1 U.S. Pat. No. 4,028,402 discloses the dichloroacetic acid salt of metformin. PA1 the p-chlorophenoxyacetic acid salt of metformin as disclosed in U.S. Pat. No. 4,835,184; PA1 pamoate salt of metformin as disclosed in French Patent Nos. 2320735 and 2037002; PA1 the orotate salt of metformin as disclosed in French Patent No. 2264539 and Japanese Patent No. 66008075; PA1 the (4-chlorophenoxy)isobutyrate salt of metformin as disclosed in French Patent No. 2275199; PA1 the clofibrate salt of metformin as disclosed in U.S. Pat. No. 4,080,472; PA1 the acetylsalicylate salt of metformin as disclosed in U.S. Pat. No. 3,957,853; PA1 the theophyllin-7-acetate salt of metformin as disclosed in French Patent No. 2220256; PA1 nicotinic acid salt of metformin as disclosed in German Patent Nos. 2357864 and 1967138; PA1 the adamantoate salt of metformin as disclosed in U.S. Pat. No. 3,903,141; PA1 the zinc-chlorophyllin salt of metformin as disclosed in Japanese Patent No. 69008566; PA1 hydroxy acid salts of metformin, including salts of hydroxy aliphatic dicarboxylic acids such as mesotartaric acid, tartaric acid, mesoxalic acids, and oxidized maleates as disclosed in Japanese Patent No. 64008237; PA1 the tannic acid salt of metformin as disclosed in Japanese Patent No. 63014942; PA1 the 3-methyl-pyrazole-5-carboxylic acid (or other 5-members hetercycle carboxylic acid) salt of metformin as disclosed in Japanese Patent Nos. 87005905 and 61022071; PA1 the aryloxyalkyl carboxylic acid salts of metformin as disclosed in Romanian Patent No. 82052; PA1 the trimethoxy benzoic acid salt of metformin as disclosed in Soviet Union Patent No. 992512; PA1 the dichloroacetic acid salt of metformin as disclosed in U.S. Pat. No. 4,028,402.
All of the above salts are formed of metformin: salt in a 1:1 molar ratio.
U.S. Pat. No. 5,631,224 to Efendic et al issued May 20, 1997, discloses a combination of metformin with GLP-1(7-36) amide, or GLP-1(7-37) or a fragment thereof which retains GLP-1(7-37) activity.
Metformin has also been suggested for use in treating various cardiovascular diseases such as hypertension in insulin resistant patients (WO 9112003-Upjohn), for dissolving blood clots (in combination with a t-PA-derivative) (WO 9108763, WO 9108766, WO 9108767 and WO 9108765-Boehringer Mannheim), ischemia and tissue anoxia (EP 283369-Lipha), atherosclerosis (DE 1936274-Brunnengraber & Co., DE 2357875-Hurka, and U.S. Pat. No. 4,205,087-ICI). In addition, it has been suggested to use metformin in combination with prostaglandin-analogous cyclopentane derivatives as coronary dilators and for blood pressure lowering (U.S. Pat. No. 4,182,772-Hoechst). Metformin has also been suggested for use in cholesterol lowering when used in combination with 2-hydroxy-3,3,3-trifluoropropionic acid derivatives (U.S. Pat. No. 4,107,329-ICI), 1,2-diarylethylene derivatives (U.S. Pat. No. 4,061,772-Hoechst), substituted aryloxy-3,3,3-trifluoro-2-propionic acids, esters and salts (U.S. Pat. No. 4,055,595-ICI), substituted hydroxyphenyl-piperidones (U.S. Pat. No. 4,024,267-Hoechst), and partially hydrogenated 1H-indeno-[1,2B]-pyridine derivatives (U.S. Pat. No. 3,980,656-Hoechst).
Montanari et al, "Treatment With Lose Dose Metformin In Patients With Peripheral Vascular Disease", Pharmacological Research, Vol. 25, No. 1, 1992, discloses that use of metformin in amounts of 500 mg twice a day (b.i.d.) increased post-ischemia blood flow in a manner similar to 850 mg metformin three times a day (t.i.d.).
Sirtori et al, "Metformin Improves Peripheral Vascular Flow in Nonhyperlipidemic Patients with Arterial Disease", J. Cardiovas. Pharm., 6:914-923 (1984), discloses that metformin in amounts of 850 mg three times a day (t.i.d) increased arterial flow in patients with peripheral vascular disease.